Proteasome inhibition and mitochondrial protein import: their role in mitochondrial homeostasis

Abstract

Event Abstract Back to Event Proteasome inhibition and mitochondrial protein import: their role in mitochondrial homeostasis Natalya Shulyakova1, 2* and Linda R. Mills1, 2 1 Toronto Western Research Institute, University Health Network, Department of Genetics and Development, Canada 2 University of Toronto, Department of Physiology, Faculty of Medicine, Canada Increasing evidence suggests mitochondrial deficits contribute to the pathogenesis of neurodegenerative diseases. Since more then 99% of mitochondrial proteins are nuclear encoded mitochondrial structure and function depend upon mitochondrial protein import (MPI). Under conditions where mitochondrial protein import is inhibited mitochondrial proteins accumulate in cytoplasm. Evidence also implicates proteasome dysfunction and the excessive and/or “ectopic” accumulation of proteins in variety of neurodegenerative diseases. These findings link proteasome dysfunction and mitochondrial protein import. We hypothesized that inhibiting MPI causes the accumulation of mitochondrial proteins in the cytoplasm, which over time results in proteasome overload/dysfunction. Conversely, inhibiting proteasome function (and the consequent accumulation of mitochondrial proteins) triggers changes in MPI and activation of retrograde (mitochondria to nucleus) signalling. In differentiated PC12 cells sublethal CCCP (2µM) caused a decrease in the import of mitochondrially targeted GFP (mtGFP) and a concomitant accumulation of mtGFP in the cytoplasm. These findings indicate that inhibiting mitochondrial protein import creates conditions that favour proteasome overloading. Inhibition of proteasome function with MG115 (5µM) decreased mtGFP, mtHSP70, Tom20 and mtTFA import to mitochondria in PC12 cells, and import of mtHSP70, Tom20 and mtTFA in primary cortical neurons. In conjunction with decreased MPI, a massive accumulation of mtGFP and Tom20 was observed in cytoplasmic cellular fractions of PC12 cells. Proteasome inhibition induced non-reversible changes in mitochondrial morphology: mitochondria were punctate, and appeared to form aggregates at one pole of the cell. These results indicate that proteasome inhibition is associated with deficits in MPI, and suggest that proteasome dysfunction may disrupt mitochondrial to nuclear signalling pathways, that normally serve to coordinate changes in the expression of nuclear-encoded mitochondrial proteins and MPI. Conference: B.R.A.I.N. platform in Physiology poster day 2009, Toronto, ON, Canada, 16 Dec - 16 Dec, 2009. Presentation Type: Poster Presentation Topic: Poster presentations Citation: Shulyakova N and Mills LR (2009). Proteasome inhibition and mitochondrial protein import: their role in mitochondrial homeostasis. Front. Neurosci. Conference Abstract: B.R.A.I.N. platform in Physiology poster day 2009. doi: 10.3389/conf.neuro.03.2009.17.052 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 18 Dec 2009; Published Online: 18 Dec 2009. * Correspondence: Natalya Shulyakova, Toronto Western Research Institute, University Health Network, Department of Genetics and Development, Toronto, Canada, natalya.shulyakova@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Natalya Shulyakova Linda R Mills Google Natalya Shulyakova Linda R Mills Google Scholar Natalya Shulyakova Linda R Mills PubMed Natalya Shulyakova Linda R Mills Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.